scholarly journals Knee Osteoarthritis Progression Is Delayed in Silent Information Regulator 2 Ortholog 1 Knock-in Mice

2021 ◽  
Vol 22 (19) ◽  
pp. 10685
Author(s):  
Tetsuya Yamamoto ◽  
Nobuaki Miyaji ◽  
Kiminari Kataoka ◽  
Kyohei Nishida ◽  
Kanto Nagai ◽  
...  
Keyword(s):  
Caspase 3 ◽  
Interleukin 1 ◽  
Type Ii Collagen ◽  
Research Society ◽  
Type Ii ◽  
Interleukin 1 Beta ◽  
Wild Type ◽  
Osteoarthritis Progression ◽  
Osteoarthritis Research Society ◽  
Wild Type Control

Overexpression of silent information regulator 2 ortholog 1 (SIRT1) is associated with beneficial roles in aging-related diseases; however, the effects of SIRT1 overexpression on osteoarthritis (OA) progression have not yet been studied. The aim of this study was to investigate OA progression in SIRT1-KI mice using a mouse OA model. OA was induced via destabilization of the medial meniscus using 12-week-old SIRT1-KI and wild type (control) mice. OA progression was evaluated histologically based on the Osteoarthritis Research Society International (OARSI) score at 4, 8, 12, and 16 weeks after surgery. The production of SIRT1, type II collagen, MMP-13, ADAMTS-5, cleaved caspase 3, Poly (ADP-ribose) polymerase (PARP) p85, acetylated NF-κB p65, interleukin 1 beta (IL-1β), and IL-6 was examined via immunostaining. The OARSI scores were significantly lower in SIRT1-KI mice than those in control mice at 8, 12, and 16 weeks after surgery. The proportion of SIRT1 and type II collagen-positive-chondrocytes was significantly higher in SIRT1-KI mice than that in control mice. Moreover, the proportion of MMP-13-, ADAMTS-5-, cleaved caspase 3-, PARP p85-, acetylated NF-κB p65-, IL-1β-, and IL-6-positive chondrocytes was significantly lower in SIRT1-KI mice than that in control mice. The mechanically induced OA progression was delayed in SIRT1-KI mice compared to that in control mice. Therefore, overexpression of SIRT1 may represent a mechanism for delaying OA progression.

scholarly journals Intraperitoneal injection of the SIRT1 activator SRT1720 attenuates the progression of experimental osteoarthritis in mice

2018 ◽  
Vol 7 (3) ◽  
pp. 252-262 ◽  
Author(s):  
K. Nishida ◽  
T. Matsushita ◽  
K. Takayama ◽  
T. Tanaka ◽  
N. Miyaji ◽  
...  
Keyword(s):  
Intraperitoneal Injection ◽  
Caspase 3 ◽  
Interleukin 1 ◽  
Research Society ◽  
Primary Mouse ◽  
Osteoarthritis Progression ◽  
A Disintegrin And Metalloproteinase ◽  
Experimental Osteoarthritis ◽  
Sirt1 Activator

Objectives This study aimed to examine the effects of SRT1720, a potent SIRT1 activator, on osteoarthritis (OA) progression using an experimental OA model. Methods Osteoarthritis was surgically induced by destabilization of the medial meniscus in eight-week-old C57BL/6 male mice. SRT1720 was administered intraperitoneally twice a week after surgery. Osteoarthritis progression was evaluated histologically using the Osteoarthritis Research Society International (OARSI) score at four, eight, 12 and 16 weeks. The expression of SIRT1, matrix metalloproteinase 13 (MMP-13), a disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS-5), cleaved caspase-3, PARP p85, and acetylated nuclear factor (NF)-κB p65 in cartilage was examined by immunohistochemistry. Synovitis was also evaluated histologically. Primary mouse epiphyseal chondrocytes were treated with SRT1720 in the presence or absence of interleukin 1 beta (IL-1β), and gene expression changes were examined by real-time polymerase chain reaction (PCR). Results The OARSI score was significantly lower in mice treated with SRT1720 than in control mice at eight and 12 weeks associated with the decreased size of osteophytes at four and eight weeks. The delayed OA progression in the mice treated with SRT1720 was also associated with increased SIRT1-positive chondrocytes and decreased MMP-13-, ADAMTS-5-, cleaved caspase-3-, PARP p85-, and acetylated NF-κB p65-positive chondrocytes and decreased synovitis at four and eight weeks. SRT1720 treatment partially rescued the decreases in collagen type II alpha 1 (COL2A1) and aggrecan caused by IL-1β, while also reducing the induction of MMP-13 by IL-1β in vitro. Conclusion The intraperitoneal injection of SRT1720 attenuated experimental OA progression in mice, indicating that SRT1720 could be a new therapeutic approach for OA. Cite this article: K. Nishida, T. Matsushita, K. Takayama, T. Tanaka, N. Miyaji, K. Ibaraki, D. Araki, N. Kanzaki, T. Matsumoto, R. Kuroda. Intraperitoneal injection of the SIRT1 activator SRT1720 attenuates the progression of experimental osteoarthritis in mice. Bone Joint Res 2018;7:252–262. DOI: 10.1302/2046-3758.73.BJR-2017-0227.R1.

Aging Cartilage in Wild-Type Mice: An Observational Study

Cartilage ◽  
2020 ◽  
pp. 194760352092671
Author(s):  
Joulnar Akoum ◽  
Khadija Tahiri ◽  
Marie-Thérèse Corvol ◽  
Didier Borderie ◽  
François Étienne ◽  
...  
Keyword(s):  
Walking Speed ◽  
Articular Surface ◽  
Type Ii Collagen ◽  
Research Society ◽  
Male Mice ◽  
Wild Type ◽  
Calcified Cartilage ◽  
Age Related ◽  
Wild Type Male ◽  
Osteoarthritis Research Society

Objective To describe the spontaneous evolution of age-related changes affecting knee joint articular cartilage, walking speed and a serum biomarker of cartilage remodeling in C57BL/6-JRj wild-type male mice. Design Histological changes were assessed by the Osteoarthritis Research Society International (OARSI) score (0=normal, 6=vertical clefts/erosion to the calcified cartilage extending >75% of the articular surface) in newborn, 1-week- and 1-, 3-, 6-, 9- and 12-month-old C57BL/6-JRj wild-type male mice, walking speed by the Locotronic system, and serum C-terminal telopeptide of type II collagen (CTX-II) content by ELISA in 1-, 3-, 6-, and 9-month-old C57BL/6-JRj wild-type male mice. Results Mean (SD) OARSI score significantly increased from 0.2 (0.3) to 1.3 (0.6) ( p=0.03) between 1 and 3 months of age and from 1.3 (0.6) to 3.3 (0.6) ( p=0.04) between 3 and 6 months of age. Mean walking speed was stable between 1 and 6 months of age but significantly decreased from 11.4 (1.8) to 3.2 (0.8) cm.s-1 ( p=0.03) between 6 and 9 months of age. Serum CTX-II content was maximal at 1 month of age, then decreased from 12.2 (8.5) to 2.4 (8.4) pg/ml ( p=0.02) between 1 and 3 months of age, remaining low and stable thereafter. Conclusions C57BL/6-JRj wild-type male mice showed continuously increasing osteoarthritic changes but delayed decreasing walking speed with age. These variations were maximal between 3 and 9 months of age. Maximal serum CTX-II content preceded these changes.

scholarly journals Independent binding of interleukin-1 alpha and interleukin-1 beta to type I and type II interleukin-1 receptors.

1993 ◽  
Vol 268 (4) ◽  
pp. 2513-2524
Author(s):  
J. Slack ◽  
C.J. McMahan ◽  
S. Waugh ◽  
K. Schooley ◽  
M.K. Spriggs ◽  
...  
Keyword(s):  
Interleukin 1 ◽  
Type I ◽  
Type Ii ◽  
Interleukin 1 Beta

scholarly journals Elevated lymphotoxin-α (TNFβ) is associated with intervertebral disc degeneration

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Zhu Guo ◽  
Chensheng Qiu ◽  
Christina Mecca ◽  
Yang Zhang ◽  
Jiang Bian ◽  
...  
Keyword(s):  
Intervertebral Disc ◽  
Cell Viability ◽  
Disc Degeneration ◽  
Intervertebral Disc Degeneration ◽  
Caspase 3 ◽  
Type Ii Collagen ◽  
Type Ii ◽  
Optimal Conditions ◽  
Cell Degeneration ◽  
Lymphotoxin Α

Abstract Background Intervertebral disc degeneration (IVDD) is a primary cause of degenerative disc diseases; however, the mechanisms underlying the degeneration remain unclear. The immunoinflammatory response plays an important role in IVDD progression. The inflammatory cytokine lymphotoxin-α (LTα), formerly known as TNFβ, is associated with various pathological conditions, while its role in the pathogenesis of IVDD remains elusive. Methods Real-time quantitative polymerase chain reaction (RT-qPCR), Western blotting (WB), and enzyme-linked immunosorbent assays were used to assess the levels of LTα in human nucleus pulposus (NP) tissues between degeneration and control groups. The plasma concentrations of LTα and C-reactive protein (CRP) were compared between healthy and IVDD patients. Rat primary NP cells were cultured and identified via immunofluorescence. Methyl-thiazolyl-tetrazolium assays and flow cytometry were used to evaluate the effects of LTα on rat NP cell viability. After NP cells were treated with LTα, degeneration-related molecules (Caspase-3, Caspase-1, matrix metalloproteinase (MMP) -3, aggrecan and type II collagen) were measured via RT-qPCR and WB. Results The levels of both the mRNA and protein of LTα in human degenerated NP tissue significantly increased. Plasma LTα and CRP did not differ between healthy controls and IVDD patients. Rat primary NP cells were cultured, and the purity of primary NP cells was > 90%. Cell experiments showed inversely proportional relationships among the LTα dose, treatment time, and cell viability. The optimal conditions (dose and time) for LTα treatment to induce rat NP cell degeneration were 5 μg/ml and 48 ~ 72 h. The apoptosis rate and the levels of Caspase-3, Caspase-1, and MMP-3 significantly increased after LTα treatment, while the levels of type II collagen and aggrecan were decreased, and the protein expression levels were consistent with their mRNA expression levels. Conclusions This study demonstrated that elevated LTα is closely associated with IVDD and that LTα may induce NP cell apoptosis and reduce important extracellular matrix (ECM) proteins, which cause adverse effects on IVDD progress. Moreover, the optimal conditions for LTα treatment to induce NP cell degeneration were determined.

Experimental Observation of the Sequence of Tibial Plateau Chondrocyte and Matrix Degeneration in Spontaneous Osteoarthritis in Guinea Pigs

2020 ◽  
Author(s):  
XIAOJIAN WANG ◽  
XIAOJIAN Wang ◽  
Lei Wei ◽  
Yan Xue ◽  
Rong-shan Li
Keyword(s):  
Knee Osteoarthritis ◽  
Guinea Pigs ◽  
Tibial Plateau ◽  
Caspase 3 ◽  
Physiological State ◽  
Research Society ◽  
Cartilage Tissue ◽  
Knee Oa ◽  
The Matrix ◽  
Osteoarthritis Research Society

Abstract Background To observe the sequence of chondrocyte degeneration and matrix degradation in the superficial surface cartilage of the tibial plateau in guinea pigs with spontaneous knee osteoarthritis (OA).Methods Forty guinea pigs were euthanized at the ages of 10 months (n=20) and 12 months (n=20). The degree of degeneration of the tibial plateau cartilage was evaluated by Osteoarthritis Research Society International (OARSI) score.The levels of MMP-13 and Caspase-3 in the chondrocytes were detected by immunohistochemistry (IHC). The serum concentration of CTX-II was measured and compared.Western blot analysis was used to detect the levels of MMP-13 and Caspase-3 in the cartilage tissue.Results The OARSI score in the 10-month-old group(6.4±1.7) was lower than that in the 12-month-old group(12.7±3.2)(P＜0.05). Immunohistochemical staining confirmed the levels of MMP-13(10-month-old,6.1±2.0;12-month-old,5.8±1.6) and Caspase-3(10-month-old,2.6±0.6;12-month-old,2.8±0.9) in two groups appeared to be nonsignificant (all P＜0.05).The serum CTX-II in the 10-month-old group(8.6±1.2) was lower than that in the 12-month-old group(13.7±2.3) (P＜0.05). The western blot results confirmed the levels of MMP-13(10-month-old,0.82±0.21;12-month-old,0.86±0.27) and Caspase-3(10-month-old,0.22±0.07;12-month-old,0.20±0.08) in two groups appeared to be nonsignificant (all P＜0.05).Conclusion The superficial chondrocytes of the tibial plateau first appeared to be hypertrophic and then apoptotic, and the matrix was further degraded when spontaneous knee osteoarthritis occurred in guinea pigs.Changes in the physiological state of chondrocytes are the initiating factors in the pathogenesis of knee OA.

scholarly journals Inhibition of Knee Osteoarthritis Progression in Mice by Administering SRT2014, an Activator of Silent Information Regulator 2 Ortholog 1

Cartilage ◽  
2020 ◽  
pp. 194760351990079 ◽  
Author(s):  
Nobuaki Miyaji ◽  
Kyohei Nishida ◽  
Toshikazu Tanaka ◽  
Daisuke Araki ◽  
Noriyuki Kanzaki ◽  
...  
Keyword(s):  
Immunohistochemical Analysis ◽  
Research Society ◽  
Control Group ◽  
Injection Group ◽  
Osteoarthritis Progression ◽  
Osteoarthritis Research Society ◽  
New Treatment ◽  
Related Proteins ◽  
Sirt1 Activator

Objective Previous findings suggest that silent information regulator 2 ortholog 1 (SIRT1) plays essential roles in chondrocytes and prevents osteoarthritis (OA) development. The purpose of this study was to investigate the effects of intraperitoneal (i.p.) and intra-articular (i.a.) administration of the SIRT1 activator SRT2104, which has been approved for use in humans. Design OA was induced by destabilizing the medial meniscus in the knee joint of 12-week-old CL57BL/6J mice. The mice were divided into 3 groups, that is, the control group, SRT2104 i.p.-injection group, and SRT2104 i.a.-injection group. Tissues were harvested at 4, 8, 12, and 16 weeks postsurgery. OA progression was evaluated using the Osteoarthritis Research Society International (OARSI) score. The production of OA-related proteins in cartilage and synovium was examined by immunohistochemistry. Results OARSI scores in the control group were significantly higher at 8 and 12 weeks compared with other 2 groups. Immunohistochemical analysis showed that Sirt1 and type-2 collagen significantly increased, whereas MMP-13, ADAMTS-5, IL-1β, IL-6, cleaved caspase 3, PARP p85, acetylated NF-κB p65, and iNOS decreased significantly in cartilage tissues from the i.p. and i.a, SRT2104 groups. In the synovium, more iNOS-positive M1-like macrophages were observed in the control group than in the i.p. and i.a, SRT2104 groups, whereas more CD206-positive M2-like macrophages were detected in the i.p. and i.a. SRT2104 groups. Conclusions Both i.p. and i.a. SRT2104 injection reduced OA progression in the mouse OA model, suggesting that SRT2104 can serve as a new treatment for OA.

Mir-149 Promotes Survival and Differentiation of Bone Marrow Mesenchymal Stem Cells by Regulating Interleukin-6/Signal Transducer and Activator of Transcription 3 Signaling Pathway

2019 ◽  
Vol 9 (8) ◽  
pp. 1160-1166
Author(s):  
Guozhong Qin ◽  
Shaochuan Huo ◽  
Juehui Li ◽  
Yin Lian ◽  
Xiaoli Jin
Keyword(s):  
Bone Marrow ◽  
Signaling Pathway ◽  
Caspase 3 ◽  
Type Ii Collagen ◽  
Type Ii ◽  
Alp Activity ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
Marrow Mesenchymal Stem Cells ◽  
Sirna Group

Bone marrow mesenchymal stem cells (BMSCs) can self-renew with multi-directional differentiation. Mir-149 is involved in various diseases, but whether Mir-149 regulates the survival and differentiation of BMSCs and related mechanisms remains unclear. BMSCs were isolated and randomly divided into Si-NC group, Mir-149 siRNA group, and Mir-149 siRNA + STAT3 inhibitor WP1066 group followed by analysis of the expression of Mir-149, RUNX2 and OPN mRNA by real time PCR, BMSCs proliferation by MTT assay, Caspase 3 activity, ALP activity, formation of type II collagen and IL-6 level by ELISA, as well as STAT3 signaling pathway expression by Western blot. Mir-149 expression was reduced in BMSCs of Mir-149 siRNA group, with promoted survival of BMSCs, decreased Caspase 3 activity, increased expression of RUNX2 and OPN, type II collagen formation, ALP activity, IL-6 secretion, as well as elevated pSTAT3 phosphorylation. The differences were statistically significant compared to Si-NC group (P < 0.05). Mir-149 siRNA + WP1066 inhibited pSTAT3 phosphorylation, reduced BMSCs survival, increased Caspase 3 activity, decreased RUNX2 and OPN expression, type II collagen production, ALP activity, as well as reduced IL-6 secretion. Compared with Mir-149 siRNA group, there were significant differences (P < 0.05). Down-regulation of Mir-149 in BMSCs can promote BMSCs survival and osteogenic differentiation by regulating IL-6/STAT3 signaling pathway.

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